ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.2T>G (p.Met1Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.2T>G (p.Met1Arg)
Variation ID: 51385 Accession: VCV000051385.74
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32316462 (GRCh38) [ NCBI UCSC ] 13: 32890599 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 1, 2014 Feb 20, 2024 May 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Met1Arg missense initiator codon variant NC_000013.11:g.32316462T>G NC_000013.10:g.32890599T>G NG_012772.3:g.5983T>G NG_017006.2:g.3902A>C LRG_293:g.5983T>G LRG_293t1:c.2T>G LRG_293p1:p.Met1Arg U43746.1:n.230T>G - Protein change
- M1R
- Other names
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- Canonical SPDI
- NC_000013.11:32316461:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18445 | 18602 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2023 | RCV000044102.25 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 2, 2015 | RCV000113010.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2022 | RCV000131870.14 | |
Pathogenic (2) |
criteria provided, single submitter
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May 16, 2023 | RCV000759594.12 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326799.5
First in ClinVar: Apr 01, 2014 Last updated: Sep 03, 2023 |
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Pathogenic
(Feb 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916857.4
First in ClinVar: Jun 02, 2019 Last updated: Sep 03, 2023 |
Comment:
Variant summary: BRCA2 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: BRCA2 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. RT-PCR analysis showed the variant to result in no aberrant splicing (Santos_2014). However, this variant abolishes the normal initiation codon of the BRCA2 protein and the next ATG is in exon 4. This might lead to an out-of-frame protein lacking important domains for transactivation and phosphorylation of BRCA2 (Santos_2014). The variant allele was found at a frequency of 8e-06 in 251342 control chromosomes (gnomAD). c.2T>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Fernandes_2016, Labidi-Galy_2017, Rebbeck_2018, Cipriano_2019, Felix_2022), however in one family the variant was absent in one affected individual, indicating a lack of segregation (Santos_2014). Overall, these data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889013.4
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
The BRCA2 c.2T>G variant disrupts the translation initiation codon of the BRCA2 mRNA and is predicted to interfere with BRCA2 protein synthesis. This variant has … (more)
The BRCA2 c.2T>G variant disrupts the translation initiation codon of the BRCA2 mRNA and is predicted to interfere with BRCA2 protein synthesis. This variant has been reported in the published literature in multiple families affected with breast and/or ovarian cancer (PMID: 24916970 (2015), 29084914 (2018), 29446198 (2018), 30535581 (2019), and 35353237 (2022)). It is predicted to be damaging to protein function (PMID: 24607278 (2014)). The frequency of this variant in the general population, 0.000008 (2/251342 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683520.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the translation initiation codon of the BRCA2 protein and is expected to result in an absent or non-functional protein product. The next … (more)
This variant disrupts the translation initiation codon of the BRCA2 protein and is expected to result in an absent or non-functional protein product. The next in-frame methionine is located at codon 124, but it is not known if a functional BRCA2 protein product can be produced using p.Met124 as an alternative translation start site. This variant has been reported in several individuals affected with breast and/or ovarian cancer (PMID: 24607278, 24916970, 27553368, 29084914, 30535581, 31263500, 33008098). This variant has been identified in 2/251342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Nov 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000072115.11
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51385). Disruption of the initiator codon … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51385). Disruption of the initiator codon has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 14647210, 18182601, 21769658, 24156927, 24607278, 24916970, 25330149; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80358547, gnomAD 0.006%). This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine is located at codon 124. (less)
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Pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Genetics Program, Instituto Nacional de Cancer
Accession: SCV002515237.2
First in ClinVar: Nov 19, 2022 Last updated: Sep 03, 2023 |
Geographic origin: Brazil
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Pathogenic
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186925.8
First in ClinVar: Aug 06, 2014 Last updated: Sep 03, 2023 |
Comment:
The p.M1? pathogenic mutation (also known as c.2T>G) is located in coding exon 1 of the BRCA2 gene and results from a T to G … (more)
The p.M1? pathogenic mutation (also known as c.2T>G) is located in coding exon 1 of the BRCA2 gene and results from a T to G substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Santos C et al. J. Mol. Diagn. 2014 May;16(3):324-34; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838716.3
First in ClinVar: Oct 10, 2018 Last updated: Sep 03, 2023 |
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Pathogenic
(Feb 20, 2004)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline,
unknown
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000145997.3
First in ClinVar: Apr 01, 2014 Last updated: Sep 03, 2023 |
Observation 1:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Latino
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002029148.2
First in ClinVar: Dec 04, 2021 Last updated: Sep 03, 2023 |
Comment:
Variant interpreted as Pathogenic and reported on 12-20-2010 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 12-20-2010 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Family history (present)
Indication for testing: Presymptomatic, Family Testing
Age: 20-29 years
Sex: female
Testing laboratory: Myriad Genetic Laboratories, Inc., Myriad Genetic Laboratories, Inc.
Date variant was reported to submitter: 2010-12-20
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service. | Matta BP | Scientific reports | 2022 | PMID: 36329109 |
Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil. | Felix GES | Breast cancer research and treatment | 2022 | PMID: 35353237 |
Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2. | Barbosa A | Cancers | 2020 | PMID: 33008098 |
Challenges in Managing Patients with Hereditary Cancer at Gynecological Services. | Ueda M | Obstetrics and gynecology international | 2019 | PMID: 31263500 |
Mutation screening of TP53, CHEK2 and BRCA genes in patients at high risk for hereditary breast and ovarian cancer (HBOC) in Brazil. | Cipriano NM Jr | Breast cancer (Tokyo, Japan) | 2019 | PMID: 30535581 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. | Labidi-Galy SI | Clinical cancer research : an official journal of the American Association for Cancer Research | 2018 | PMID: 29084914 |
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. | Fernandes GC | Oncotarget | 2016 | PMID: 27741520 |
Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity. | Pinto P | Breast cancer research and treatment | 2016 | PMID: 27553368 |
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. | Cybulski C | Clinical genetics | 2015 | PMID: 25330149 |
The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. | Peixoto A | Clinical genetics | 2015 | PMID: 24916970 |
Pathogenicity evaluation of BRCA1 and BRCA2 unclassified variants identified in Portuguese breast/ovarian cancer families. | Santos C | The Journal of molecular diagnostics : JMD | 2014 | PMID: 24607278 |
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. | Tea MK | Maturitas | 2014 | PMID: 24156927 |
Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. | Thomassen M | Breast cancer research and treatment | 2012 | PMID: 21769658 |
Variation of breast cancer risk among BRCA1/2 carriers. | Begg CB | JAMA | 2008 | PMID: 18182601 |
A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. | Jakubowska A | European journal of human genetics : EJHG | 2003 | PMID: 14647210 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
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Text-mined citations for rs80358547 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.